Pharmaceutical tablet



United States Patent 3,102,845 PHARMACEUTICAL TABLET John RichardFennel], Lansdale, Pa., assignor to McNeil Laboratories, Incorporated, acorporation of Pennsylvania No Drawing. Filed Nov. 18, 1960, Ser. No.70,132 17 Claims. (Cl. 16782) This invention relates to \a novelpharmaceutical tablet formulation and to methods for its preparation.

Numerous and highly intricate methods are currently being employed inthe pharmaceutical industry for the preparation of pharmaceuticalshaving the peculiar property of exerting pharmacological activity over acontrolled time period. The purpose for this, obviously, is to minimizethe number of times a patient is required to take medication during agiven day and, perhaps more importantly, to ensure constant absorptionof therapy over a given time period, thus avoiding peaks and valleys inthe control of chronic and acute maladies.

One of the most commonly employed methods for obtaining a so-calledprolonged therapeutic effect from a pharmaceutical formulation is tocombine the active ingredients during the manufacturing process with oneor more inert components in such a fashion that the release of theactive drug from the total pharmaceutical mass during its passagethrough the stomach and intestinal tract, is even and gradual. Amonginert components which are presently being used for such purposes arehigh molecular weight waxes, used singly or in various combinations,either evenly distributed among the active ingredients or first meltedand then carefully coated over small particles of the active components.

One disadvantage in the use of waxes for long-acting tablet formulationsis that a relatively large mass of wax must be incorporated in thedosage form to give the desired long-acting effect. In other words, theratio of Wax to active component is a several-fold factor, thusrequiring the manufacture of such a bulky tablet that its ingestion bypatients is relatively difficult and uncomfortable.

It can readily be seen, therefore, that one of the prevailing problemsin the pharmaceutical development field is the manufacture ofcontrolled-release dosage forms which contain inert components that havelarge surface area, are nonabsorbable, and are devoid of toxicity andundesirable side effects.

The use of alkaline earth metal salts of fatty acids in tabletmanufacture is known. These substances have been used for many years astablet lubricants. That is to say, they are incorporated in the finaltablet granulation just prior to compression in relatively smallquantities in order to facilitate compression of the granules withouttheir adherence to the punches and dies in the tabletting machine.

It is also known that saturated fatty acids themselves, their esters,ethers and alcohols, can be pelletized with polyvinylpyrrolidone byconverting the polymer, in the presence of the fatty acid or itsderivative, into a molten mass, granulating the congealed mass,reheating, cooling, adding the therapeutic and pelletizing at atemperature near the set oint.

, Among the many disadvantages in using fatty acids or their derivativesin combination with polyvinylpyrrolidone to prepare prolonged actiondosage unit forms is their physical similiarity to high molecular weightwaxes. In order to get uniform distribution in polyvinylpyrrolidone, thefatty acid derivatives must be melted in the presence of the latter,granulated, remelted and then pelletized. This not only constitutes anunwieldly, lengthy and expensive process but also, because of the dualhigh temperature involvement, limits the process to incorporation onlyof those therapeutically active agents which can safely withstandelevated temperature exposure without decomposition. Thus, as in thecase of most high molecular weight waxes, the long chain fatty acids andtheir derivatives are not susceptible to conventional wet granulation atroom temperature.

The fatty acid derivatives above mentioned bear yet another similarityto high molecular weight waxes in their use as vehiclse for long-actingdosage forms. Because of their physical character, large quantifies ofthe fatty acid substances must be employed to obtain the desired effect.Thus the proportion of P.V.P. to fatty acid material must be about oneto seven, or more, Moreover, it is known that the fatty acids themselvesare inadequate as long-acting vehicle matrices, even though combinedwith P.V.P. Thus it is frequently necessary, in order to obtain thedesired prolonged effect, to incorporate a quantitiy of high molecularweight want such as candelilla, beeswax or carnauba in the formulation.This adds still further to the bulkiness of the dosage form,unnecessarily increasing the volume of the total mass and making theoral ingestion of the medication that much more diflicult.

It has now been discovered that by combining an earth or alkaline earthmetal salt of a. fatty acid in certain proportions withpolyvinylpyrrolidone, a result is obtained which, heretofore, defiedsuccessful accomplishment by those skilled in the art. The novelformulation of this invention embraces a dosage unit combination capableof releasing incorporated medication gradually over a controlled periodof time. Among other advantages of the novel combination is that,depending upon the ratio of polyviniylpyrrolidone (P.V.P.) to fatty acidsalt employed, the release of a drug from the tablet matrix can bepredictably controlled over a desired, extended time span. The novelcombination eliminates the use of waxes, does not need high temperaturesfor formulation, reduces the total number of steps in the manufacturingoperation and requires no special machinery or equipment. In otherwords, by simple variation of P.V.P.'fatty acid salt proportions withinthe prescribed limits, one can regulate drug release from a relativelyshort (1 to 2 hours) to long (24 hours) time interval. In addition. thenovel combination permits the use of the wet granulation process withoutalteration of the hydrophobic nature of the fatty acid salt. This isaccomplished by taking advantage of the unique water soluble,film-forming properties of P.V.P through its incorporation with thefatty acid salt in the prescribed ratios.

The novel combination of the present invention comprises, as theprincipal constituents of an oral tablet formulation, therapeuticingredient(s) distributed throughout a moleoularly dispersed P.V.P.phase, and forming a film network about a water insoluble, hydrophobic,fatty acid salt macrophase, the P.V.P.-fatty acid salt constituentsbeing in a ratio of from about 1 to about 0.5 to 4. It will be observedthat although the ratio of P.V.P. to fatty acid salt is critical, it maybe varied over a substantial range, depending upon the rate of releaseof medicament desired. Thus, when the ratio is from about I to about 0.5to 1, release of the medicament is obtained in approximately one tothree hours. When the ratio is from about 1 to about 1.5 to 2.0, theincorporated medicament is released over a period of from about seven totwelve hours. When the ratio is from. about 1 to about 3 to 4, releaseis obtained in a period of from about fourteen to twenty-fourhours.

Although the mechanism whereby gradual release of medication is attainedover an extended time period from the novel combination of thisinvention has not been absolutely determined, it can be postulated withreasonable certainty that the desired effect is gained because of thepeculiar physical combination of components, and their co-action duringabsorption in the gut. This unusual combination is accomplished throughthe manufacturing process which comprises, in a general way, theaddition of a sufficient volume of water to wet the dry powdered masscontaining the prescribed quantity of fatty acid salt, P.V.P. andtherapeutic components as well as other tablet constituents, if desired.The medicament dissolves in the added water and becomes evenlydistributed throughout the P.V.P. The medicament-P.V.P.-water systemthen flows freely about the hydrophobic fatty acid salt macroparticles.Upon drying, a plasticized, molecular film layer of P.V.P. andmedicament is deposited about the fatty acid salt particles. The driedgranules and, consequently, the final tablet are composed of a networkof hydrophobic fatty acid salt particles, enveloped by a hydrophilic,medicated P.V.P. film. The granules are uniformly distributed throughoutthe tablet mass, hence the drug molecules are also uniformly distributedthroughout the mass.

When the above-described dosage form comes in contact with digestivejuices, the aqueous medium infiltrates the hydrophobic fatty acid saltmass at a slow, constant rate by following the network path of thehydrophilic P.V.P. film through capillary action. The molecules ofmedicament are dissolved in the juice at the point of contact of thelatter with the drug-containing P.V.P. film. The dissolved medicament isthen free to diffuse into the body of the surrounding medium and isavailable for absorption. Because of this method of diffusion of drugout of the tablet, there is no rupture of the fatty acid salt mass, andthe tablet functions as an inert matrix whose shape remainssubstantially intact after prolonged agitation in fluid media.

It is to be observed that two competing forces are operating within thetablet as it tumbles in the intestinal tract and is bathed in he aqueousfluid-namely, the hydrophobic barrier of the fatty acid salt and thesurrounding hydrophilic film of P.V.P. and medicament. As a result, thedissolution of water soluble therapeutics is readily controlled byincreasing or decreasing the quantity of hydrophobic material in thetablet. In other words, by having a relatively high propo-riton of fattyacid salt, as compared to P.V.P. content, the medicament will bereleased over a long period of time. On the other hand by decreasing theratio, the therapeutic component is released over a shorter period oftime. Advantage is thus taken of the unique hydrophilic, nonswellingfilm properties of P.V.P. as contrasted to the action of other commonlyused binders which do not possess such physical properties.

The polyvinylpyrrolidone component which is preferred in the novelcombination of this invention is one having a K-value of from about 24to about 40 and having an average molecular Weight of from about 20,000to about 100,000, preferably about 40,000 to about 80,- 000. As thefatty acid salt, any one of the nontoxic, pharmaceutically acceptableearth, alkaline earth metals may be employed, as for example calcium,magnesium or aluminum.

Although the novel formulation is peculiarly adapted to the use of watersoluble medicaments, it may be readily modified to include waterinsoluble therapeutics, singly, in combination with each other or incombination with water soluble medicaments, and it is intended that thismodification be included within the scope of the present invention.Inasmuch as a water insoluble drug can be made available for absorptionfrom the intestinal tract only by being directly exposed to theintestinal mucosa, such exposure can be accomplished by incorporating inthe formulation an appropriate amount of hydrophilic gum. The quantityof the hydrophilic gum should be such that the tablet matrix erodesslowly while tumbling through the intestinal tract, thereby renderingthe water insoluble drug available for absorption. The exact amount ofhydrophilic gum may be varied depending upon the nature of the waterinsoluble constituent and its quantity in relation to the total tabletmass. In practice one may employ from about 0.1% to about 10% of thegum, preferably from about 0.5% to about 5%. Gums suitable for thispurpose include gelatin, the methylcelluloses, including thecarboxymethylcellulose, and their salts such as the sodium salt, acaciaand the alginates.

in a general way, therefore, the novel tablet formula tion comprises awater soluble or water insoluble therapeutic component in intimatedispersion throughout a molecular P.V.P. phase which is uniformlydistributed in layer form about macroparticles of a water insolublefatty acid salt. It will be readily apparent, therefore, that the noveltablet formulation lends itself to a wide variety of applications in thepharmaceutical field since it provides a means for administering watersoluble and water insoluble therapeutics singly, in admixture with eachother or with other substances, over a controlled period of time withpredictable regularity and time lag. Drugs which are suitable for use inthe novel tablet formulation include antihistaminics, such ascarbinoxamine and rotoxamine; antispasmodics, such as poldine; centralnervous system depressants, such as phenobarbital, butylbarbital',central nervous system stimulants, such as methamphetamine;vasodilators, such as phenylpropanolamine, phenylephrine; vitamins, suchas thiamine and pyridoxine; antibiotics, such as tetracycline,chlortetracycline, oxytetracycline, penicillin and derivatives thereof,such as potassium e-phenoxyethyl penicillin. These may be incorporatedin the novel formulation either in the form of their water insolublebases or their water soluble salts, depending upon the particularmodification selected and found most advantageous.

It is to be emphasized that, although a fatty acid salt is used as acritical component in rendering the tablet mass long acting, thisquantity of salt is incorporated during the wet granulation process.That is to say, it is included in the powdered mass during that step oftablet manufacture whereby it is, along with other ingredients, wettedwith water and becomes an integral component of the dried granules.However, those who are familiar with tablet manufacturing process knowthat fatty acid salts, especially calcium stearate, are used routinelyas tablet lubricants. In this capacity, the fatty acid salts areincorporated at that stage of tablet manufacture just prior tocompression and after drying and reduction of granules to theappropriate size. Accordingly, although fatty acid salts, such ascalcium stearate, are used in the present formulation as the criticalcomponents which render the tablet long acting, these same salts mayalso be used as lubricants by incorporating them in appropriateadditional small quantities in the dried granulation just beforecompression. In some cases it may be desirable to employ otherlubricants in the tablet granulation, such as, for example, the fattyacids themselves, i.e. stearic acid, talc or mixtures thereof.

There is no restriction on the inclusion of other commonly employedexcipients in the formulation of the novel combination of thisinvention. Thus, one may employ as diluents, in whatever quantities areindicated, such components as dibasic calcium phosphate, lactose,mannitol and others. One may also include as binders, to ensureadditional cohesive properties over and above those exerted by P.V.P.,such gums as acacia or tragacanth.

The unique time-controlled properties of the novel combination of thisinvention are readily demonstrable by subjecting the formulated tabletsto release-rate studies in accordance with the method described in theUnited States Pharmacopeia (U.S.P. XV) or the method described by Soudcret 211., Drug Standards, 26, 77 (1958). Table I, below, shows theresults obtained in release-rate studies employing the U.S.P. tabletdisintegration apparatus with discs. Table II, below, shows the releaserates obtained with various drugs over a twenty-four-hour period,employing the Souder et al. method. It will be readily seen from theresults of these studies that the rate of release of the therapeuticcomponent can be accurately controlled over whatever periods of time aredesired by incorporating, in proper proportion, P.V.P. and a fatty acidsalt in the tablet granulation. Finally, Table III shows resultsobtained, in terms of cumulative percent of drug released with respectto time, when a water-id soluble drug is incorporated in thenovelformulation together with specific quantities of carboxyrnethylcellulosesalts (Eaxmples IV and VII). In order to demonstrate the effectivenessof gums such :as the methylcelluloses when used for this purpose, i.e.in combination with waterinsoluble therapeutics, comparison is made witha formw lation wherein such gum is absent (Example VIII). The tabletdisintegration apparatus used was that described in United StatesPharmacopeia, XV, revision.

EXAMPLE II F ormula: Percent l Rotoxamine D-tartrate 1.1370 (2Polyvinylpyrrolidone 5 .0 3) Calcium stearate 10.0

Formula: Percent (1) Phenylephrine HCl 1.875 (2) Polyvinylpyrrolidone 5.0 (3) Calcium stearate 20.0

(4) Dibasic calcium phosphate, hydrous 72.625 (5) Calcium stearate 0.5

(1) (2) (3) (4) are wetted with water and pressed TABLE I CumulativePercent of Drug Released Ratio of P.V.P. to Calcium Steal-ate Drug I 2 34 5 ii 7 8 24 hr. hrs hrs. hrs. hrs. hrs. hrs hrs. hrs.

1 Rotoxamlne D-tertrate 54 90 100 1: d0 28 38 4b 56 63 72 78 87 9? (41)1:2 with 2% CMC. Chlorzoxazone (Water insoluble)- 11 26 33 71 (e) 1:Rotoxamine D-tnrtrate 33 47 56 60 91 (j) l: 28 36 48 56 60 64 74 TABLEII Cumulative Percent 01 Drug Released Ratio of P.V.P. Drug to CalciumSteal-ate 1 3 5 6 7 M hr. hrs. hrs hrs. hrs hrs.

(a) 111.5 Poldine Methylsnliate 38 66 84 100 (0) 1:1.5 CarbiuoxarnineMeleate... 42 70 S6 100 (0)111] Poldine Methylsuliaten. 33 63 B4 100((1) 1:2. (1 26 65 80 100 (e) 1:2. 29 56 79 86 (f) 1: 24 44 61 87 TABLEIII Cumulative Percent of Drug Released vs. Time-U.S.P. TabletDisintegration Apparatus l A Btt c!!! 1 Hour 11 5B 2 Hours. 26 100 3Hours.-- 33 7 Hours 71 Manner of tablet disintegration:

A*-Tablet substantially unchanged after seven hours. (Formula- Lion ofExample VIII.)

(Formulation of Example IV.)

B"-Slow "erosion" 0i tablet. C"*"-Fast erosion" of tablet. (Formulationof Example VII.)

The following examples are intended to illustrate but not to limit thescope of the present invention.

EXAMPLE I Formula:

Percent (l) Poldine methylsulfate 1.545 (2) Polyvinylpyrrolidone 10.0(3) Calcium stearate 15.0

(4) Dibasie calcium phosphate, hydrous- 72.955 (5) Calcium stearate 0.5

(l) (2) (3) (4) are wetted with water and pressed through a screen. Theresulting granules are air dried at about 100 F., again passed through ascreen; (5) is admixed, and the entire mass is compressed into tablets.

through a screen. The resulting granules are air dried at about F.,again passed through a screen; (5) is admixed, and the entire mass iscompressed into tablets.

EXAMPLE IV Formula: Percent 1) Chlorzoxazone 62.5 (2) Sodiumcarboxyrnethylcellulose 2.0 3) Calcium stearate 20.0 4)Polyvinylpyrrolidone 10.0 (5) Dibasic calcium phosphate, hydrous 5.0 (6)Calcium stearate 0.5

(1) (2) (3) (4) (5) are wetted with water and pressed through a screen.The resulting granules are air dried at about 100 F., again passedthrough a screen; (6) is admixed, and the entire mass is compressed intotablets.

(l) (2) (3) (4) are wetted with water and pressed through a screen. Theresulting granules are air dried at about 100 F., again passed through ascreen; (5) is admixed, and the entire mass is compressed into tablets.

sac-gees EXAMPLE V1 Formula: Percent 1) Carbinoxamine maleate 1.5 (2)Polyvinylpyrrolidone 10.0 (3) Calcium stearate 15.0 (4) Dibasic calciumphosphate, hydrous 73.0 (5) Calcium stearate 0.5

(1) (2) (3) (4) are wetted with water and pressed through a screen. Theresulting granules are air dried at about 100 F., again passed through ascreen; (5) is admixed, and the entire mass is compressed into tablets.

EXAMPLE VII Formula: Percent (1) Chlorzoxazone 62.5 (2)Polyvinylpyrnolidone 10.0 (3) Calcium stearate 20.0 (4) Sodiumcarboxymethylcellulose 4.0 (5) Dibasic calcium phosphate, hydrous 3.0(6) Calcium stearate 0.5

(1) (2) (3) (4) (5) are wetted with water and pressed through a screen.The resulting granules are air dried at about 100 F., again passedthrough a screen; (6) is admixed, and the entire mass is compressed intotablets.

EXAMPLE VIII Formula: Percent l Chlorzoxazone 62.5 (2)Polyvinylpyrrolidone 10.0 (3) Calcium stearate 20.0 4) Dibasic calciumphosphate, hydrous 7.0 (5) Calcium stearate 0.5

(1) (2) (3) (4) are wetted with water and pressed through a screen. Theresulting granules are air dried at about 100 F., again passed through ascreen; (5) is admixed, and the entire mass is compressed into tablets.

EXAMPLE IX Formula Percent 1) Potassium a-phenoxyethyl penicillin 49.5(2) Polyvinylpyrrolidone 10.0 (3) Calcium stearate 40.0 (4) Calciumstearate 0.5

(l) (2) (3) are mixed, wetted with a solution containing equal parts ofisopropyl alcohol and water, screened, dried, (4) is added, and themixture is compressed into tablets.

What is claimed is:

1. A compressed pharmaceutical preparation for timecontrolled oraladministration consisting essentially of the following components:polyvinylpyrrolidone, a hydrophobic fatty acid salt and therapeuticallyactive material, the composition containing a ratio of 1 partpolyvinylpyrrolidone to from about 1 part to about 4 parts hydrophobicfatty acid salt, the quantity by Weight of polyvinylpyrrolidone being atleast about 5% of the total weight of the composition.

2. A composition as set forth in claim 1 wherein the therapeuticcomponent is water soluble.

3. A composition as set forth in claim 1 wherein the therapeuticcomponent is water insoluble.

4. A composition as set forth in claim 1 wherein the fatty acid salt isan alkaline earth metal salt.

5. A compressed pharmaceutical preparation for timecontrolled oraladministration consisting essentially of the following components:polyvinylpyrrolidone, a hydrophobic fatty acid salt, thereapeuticallyactive material and a hydrophilic gum, the composition containing aratio of 1 part of polyvinylpyrrolidone to from about 1 part to about 4parts hydrophobic fatty acid salt, the quantity by Weight ofpolyvinylpyrrolidone being at least about 5% of the total weight of thecomposition.

6. A composition as set forth in claim 5 wherein the therapeuticcomponent is water soluble.

7. A composition as set forth in claim 5 wherein the therapeuticcomponent is Water insoluble.

8. A composition as set forth in claim 5 wherein the hydrophilic gum isa methylcellulose.

9. A compressed pharmaceutical preparation for timecontrolled oraladministration consisting essentially of the following components:polyvinylpyrrolidone, a hydrophobic fatty acid salt, a mixture of watersoluble and water insoluble therapeutically active materials and ahydrophilic gum, the composition containing a ratio of 1 part ofpolyvinylpyrrolidone to from about 1 part to about 4 parts hydrophobicfatty acid salt, the quantity by weight of polyvinylpyrrolidone being atleast about 5% of the total Weight of the composition.

10. A compressed pharmaceutical preparation for timecontrolled oraladministration consisting essentially of the following components:polyvinylpyrrolidone, a hydrophobic fatty acid salt and poldinemethylsulfate, the composition containing a ratio of 1 partpolyvinylpyrrolidone to from about 1 part to about 4 parts hydrophobicfatty acid salt, the quantity by weight of polyvinylpyrrolidone being atleast about 5% of the total weight of the composition.

11. A compressed pharmaceutical preparation for timecontrolled oraladministration consisting essentially of the following components:polyvinylpyrrolidone, a hydrophobic fatty acid salt and rotoxamineD-tartrate, the composition containing a ratio of 1 partpolyvinylpyrrolidone to from about 1 part to about 4 parts hydrophobicfatty acid salt, the quantity by weight of polyvinylpyrrolidone being atleast about 5% of the total weight of the composition.

12. A time-controlled oral pharmaceutical dosage composition in tabletform comprising polyvinylpyrrolidone and a hydrophobic fatty acid saltin a ratio from about 1 to about 0.5 to 4 and phenylephrinehydrochloride.

13. A compressed pharmaceutical preparation for timecontrolled oraladministration consisting essentially of the following components:polyvinylpyrrolidone, a hydrophobic fatty acid salt and phenylephrinehydrochloride, the composition containing a ratio of 1 partpolyvinylpyrrolidone to from about 1 part to about 4 parts hydrophobicfatty acid salt, the quantity by Weight of polyvinylpyrrolidone being atleast about 5% of the total Weight of the composition.

14. A compressed pharmaceutical preparation for timecontrolled oraladministration consisting essentially of the following components:polyvinylpyrrolidone, a hydrophobic fatty acid salt, chlorzoxazone and ahydrophilic gum, the composition containing a ratio of 1 part ofpolyvinylpyrrolidone to from about 1 part to about 4 parts hydrophobicfatty acid salt, the quantity by weight of polyvinylpyrrolidone being atleast about 5% of the total weight of the composition.

15. A composition as set forth in claim 14 wherein the hydrophilic gumis a methylcellulose.

16. A compressed pharmaceutical preparation for timecontrolled oraladministration consisting essentially of the following components:polyvinylpyrrolidone, a hydrophobic fatty acid salt and carbinoxaminemaleate, the composition containing a ratio of 1 partpolyvinylpyrrolidone to from about 1 part to about 4 parts hydrophobicfatty acid salt, the quantity by weight of polyvinylpyrrolidone being atleast about 5% of the total weight of the composition.

17. A composition as set forth in claim 16 wherein the methylcelluloseis carboxymethylcellulose.

(References on following page) References Cited in the file of thispatent UNITED STATES PATENTS 2,385,920 Jenkins Oct. 2, 1945 2,606,195Tilford et a1 Aug. 5, 1952 2,776,924 Martin Jan. 8, 1957 2,811,483Aterno et al Oct. 29, 1957 2,819,981 Schornstheimer et a1 Jan. 14, 19582,820,741 Endicott et a1. Jan. 21, 1958 2,841,528 Myhre July 1, 19582,887,437 Klioze et a] May 19, 1959 2,887,439 Klioze et a1 May 19, 19592,890,985 Marsh et al June 16, 1959 2,894,289 Harper et a1 July 14, 19592,895,877 Marsh July 21, 1959 2,897,120 Cronin et a1 July 28, 19592,897,121 Wagner July 28, 1959 2,918,411 Hill Dec. 22, 1959 2,957,804Shuyler Oct. 25, 1960 2,991,226 Millar et a1 July 4, 1961 3,018,221Millar et al. Ian. 23, 1962 OTHER REFERENCES Clistin, T.M. 587,051, Mar.16, 1954. Clistinal, T.M. 613,458, Oct. 4,, 1955.

Kwan et al., Factors Afiecting Tablet Disintegration, J.A.Ph.A. (Sci.Ed.), vol. 46, No. 4, pp. 236-239, April 1957.

Parafon, T.M 681,397, July 7, 1957 Nacton," T.M. 668,255, Oct. 14, 1958.

Paraflex, T.M. 668,920, Oct. 28, 1958.

Poldine," File No. 6753, recorded in T.M. search room December 17, 1958,by British Pharmacopoeia Comm; for2-benzllcyloxymethy1-l-methylpyrrolidine.

Stempel, Prolonged Drug Action, J.A.Pl1.A. (Prac. Phy. Ed.), 20(6), June1959, pp. 334-336.

Sternpel,Prolonged Drug Action, J .A.Ph.A. (Prac. Phy. Ed.), 20(7), July1959, pp. 393-395.

American Drug Index-4960," Wilson et al., J. B. Lippincott (30.,Philadelphia, Pa. 1960--Lc-55-6286, pp. 152-153, 167, 174-175, 411-412,472, 509-511, and 596, June 23, 1960.

Nactisol," trademark application S.N. 109,719, July 27, 1960.

Twistussin, trademark application S.N. 106,211, July 27, 1960.

Twiston, T.M. 702,155, Aug. 2, 1960.

1. A COMPRESSED PHARMACEUTICAL PREPARATION FOR TIMECONTROLLED ORALADMINISTRATION CONSISTING ESSENTIALLY OF THE FOLLOWING COMPONENTS:POLYVINYLPYRROLIDONE, A HYDROPHOBIC FATTY ACID SALT AND THERAPEUTICALLYACTIVE MATERIAL, THE COMPOSITION CO TAINING A RATIO OF 1 PARTPOLYVINYLPYRROLIDONE TO FROM ABOUT 1 PART TO ABOUT 4 PARTS HYDROPHOBICFATTY ACID SALT, THE QUANTITY BY WEIGHT OF POLYVINYLPYRROLIDONE BEING ATLEAST ABOUT 5% OF THE TOTAL WEIGHT OF THE COMPOSITION.